Am J Pathol：诱发肾上腺癌的基因突变

近日，来自密歇根大学综合癌症研究中心和巴西圣保罗大学的研究者通过研究发现，两个不同的遗传突变可以合作从而诱导肾上腺癌发生。这项研究为我们理解这种罕见的致死性的肾上腺癌提供了线索，而且研究者希望为开发特定的疗法提供帮助。

在美国每年大约有600人诊断出肾上腺癌（adrenal cancer），而且其往往是在癌症后期才能够被诊断出来，这样医生几乎没有足够时间治疗这种癌症，常常导致患者死亡。

研究者Gary表示，由于肾上腺癌非常罕见，因此发现足够的病人，并且提供足够的样品进行研究显得尤为困难。我们的目标是理解肿瘤的发生以及基因的突变以便我们可以开发出治疗措施来延长患者的寿命。

通过研究肾上腺组织样品中的良性和恶性肿瘤，研究者发现良性肿瘤和恶性肿瘤在两个遗传通路上存在差别：β-连环蛋白（beta-catenin）和胰岛素样生长因子2（IGF-2）。β-连环蛋白在良性肿瘤中存在高比例的突变，但是在良性肿瘤中IGF-2的上调却很罕见。从另一个角度来讲，大部分的肾上腺癌都表现出IGF-2的上调，相比仅仅有IGF-2上调的肿瘤来说，β-连环蛋白的突变的肿瘤和重病或者高死亡率直接相关。

研究者通过在肾上腺癌小鼠模型中诱发β-连环蛋白和IGF-2的单一突变或者双突变，结果发现，小鼠仅仅在双突变的时候可以发展成为癌症。相关研究成果刊登在了近日的国际杂志the American Journal of Pathology上。

下一步研究者希望通过阻挡β-连环蛋白和IGF-2通路来开发出潜在的肾上腺癌疗法。研究者表示，促使癌症的原因远远大于我们所发现的特殊基因，越来越多的遗传方法称为了新型的癌症疗法，因此未来的癌症疗法将很有可能是很多方法联合起来来发挥作用的。

编译自：Two Gene Mutations Drive Adrenal Cancer

doi:10.1016/j.ajpath.2012.05.026
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Progression to Adrenocortical Tumorigenesis in Mice and Humans through Insulin-Like Growth Factor 2 and β-Catenin

Joanne H. Heaton⁎, Michelle A. Wood⁎, Alex C. Kim⁎, Lorena O. Lima†, Ferdous M. Barlaskar⁎, Madson Q. Almeida†, Maria C.B.V. Fragoso†, Rork Kuick‡, Antonio M. Lerario†, Derek P. Simon⁎, Ibere C. Soares†, Elisabeth Starnes⁎, Dafydd G. Thomas§, Ana C. Latronico†, Thomas J. Giordano⁎, ‡, §, Gary D. Hammer⁎, ‡

Dysregulation of the WNT and insulin-like growth factor 2 (IGF2) signaling pathways has been implicated in sporadic and syndromic forms of adrenocortical carcinoma (ACC). Abnormal β-catenin staining and CTNNB1 mutations are reported to be common in both adrenocortical adenoma and ACC, whereas elevated IGF2 expression is associated primarily with ACC. To better understand the contribution of these pathways in the tumorigenesis of ACC, we examined clinicopathological and molecular data and used mouse models. Evaluation of adrenal tumors from 118 adult patients demonstrated an increase in CTNNB1 mutations and abnormal β-catenin accumulation in both adrenocortical adenoma and ACC. In ACC, these features were adversely associated with survival. Mice with stabilized β-catenin exhibited a temporal progression of increased adrenocortical hyperplasia, with subsequent microscopic and macroscopic adenoma formation. Elevated Igf2 expression alone did not cause hyperplasia. With the combination of stabilized β-catenin and elevated Igf2 expression, adrenal glands were larger, displayed earlier onset of hyperplasia, and developed more frequent macroscopic adenomas (as well as one carcinoma). Our results are consistent with a model in which dysregulation of one pathway may result in adrenal hyperplasia, but accumulation of a second or multiple alterations is necessary for tumorigenesis.